Cystic fibrosis (CF) is the most common genetic disorder in Caucasians with chronic pulmonary infection and inflammation driving the life-shortening mortality seen in CF. A central feature observed is a noxious persistent cycle of airway obstruction, infection, and inflammation. Multifarious metalloproteinases modulate proinflammatory cues in the CF airway by regulating cytokines/chemokines, which recruit and activate neutrophils that dump proteases destroying structural tissue that ultimately results in respiratory failure and death. Matrix metalloproteinase 9 (MMP9) has been shown to self-propogate itself and neutrophil recruitment via proteolytic activation of a potent chemoattractant. Furthermore, clinical data associate it with lung matrix breakdown, pulmonary disease severity, and survival. The metalloenzyme family also mediates membrane bound effector molecules such as TNF. Shedding of TNF primarily occurs chiefly through a disintegrin metalloproteinase (ADAM17). TNF-a master regulator of immune response- is elevated in CF sputum and shows an inverse relationship with lung function and survival in several clinical studies. Despite this, there is no data describing the primary metalloproteinase (ADAM17) responsible for soluble TNF inflammatory exuberance, or its endogenous antiproteinase (tissue inhibitor of metalloproteinase3, TIMP3) in CF or other chronic lung diseases. Moreover, there is a lack of safe and effective options in the CF treatment arsenal to combat the lethal airway inflammation experienced. Therefore our central hypothesis is that metalloproteinase balance regulates the host immune response, establishing a chronic inflammatory phenotype in the CF airways, and serves as a putative target to alter lung disease progression. Preliminary in vitro and in vivo evidence of an endogenous macrocyclic peptide, termed rhesus theta-defensin-1 (RTD-1) suggest it may be a novel metalloproteinase inhibitor that regulates ADAM17 and MMP9 activities thereby dampening the spread and severity of CF inflammation. In Aim1, we will describe airway metalloproteinase activity and inhibition on TNF cleavage, global lung inflammation and tissue damage control in a murine chronic infection model of CF. In parallel, Aim2, will evaluate the therapeutic efficacy of RTD-1, a putative metalloproteinase inhibitor, in this murine model. Uniquely, theta-defensins are expressed in Old World monkeys, but not in humans. They are non-toxic, non-immunogenic, highly stable, and non-immunosuppressive. We believe, RTD-1 may be resurrected for therapeutic use in human disease. This research and the application of RTD-1 as a CF therapeutic could fundamentally alter our understanding and management of CF airway disease, as well as other chronic lung disease.